[R01] Determinants of pegivirus persistence and immune control

Ente: National Institute of Allergy and Infectious Diseases

Scadenza: 2030-06-30

Importo max: 687.374 EUR

Paese: US

Descrizione

PROJECT SUMMARY/ABSTRACT Human pegivirus (HPgV) chronically infects approximately 15% of the global human population. Although HPgV does not cause overt disease, we know very little about its biology. Currently, there are no cell culture systems for cultivating HPgV in vitro and no laboratory animals are susceptible to HPgV infection. Recently, we created the first mouse model of PgV infection by adapting a rat pegivirus to infect mice. This mouse-adapted PgV (maPgV) causes high-titer viremia in wild-type mice that persists for hundreds of days without causing overt disease, closely recapitulating key features of HPgV infection. We have also shown that maPgV utilizes a highly novel, albeit still poorly defined, mechanism of viral persistence. Thus, discovering how PgVs are able to persist in otherwise immunocompetent hosts could be a useful tool to explore mechanisms of “failed immunity.” Studies to date have indicated that most wild-type mice are able to exert a degree of anti-viral immunity against maPgV infection, but this immunity is weak and insufficient to fully eradicate the infection––a phenomenon we call “semi- control.” In contrast, ~10% of wild-type mice are capable of completely clearing maPgV infection and are immune to re-challenge––a phenomenon we call “elite control.” Preliminary data suggests that lymphocytes of the adaptive immune system are responsible for both semi- and elite-control. We will leverage the tractability of the mouse host to understand both of these phenomena with the ultimate goal of defining differences between semi- and elite-controllers that govern maPgV persistence. In Aim 1 we will determine adaptive immune functions responsible for PgV semi-control, using a panel of immune-gene-knockout mice to identify the specific lymphocyte subsets and effector functions that are responsible for maPgV semi-control and performing lymphocyte depletion studies at key time points to determine the importance of different lymphocyte populations for establishment and maintenance of semi-control. We will also introduce a highly immunogenic peptide into maPgV using reverse genetics, allowing us to track virus-specific immune responses and determine whether maPgV can “hide” this antigen from the immune system. In Aim 2 we will determine adaptive immune functions responsible for PgV elite-control, we will passively confer elite control to lymphocyte-deficient mice from elite- controllers via splenocyte transfer, then break elite control in passively-immunized mice using different lymphocyte-targeting antibodies to attribute elite control to a specific lymphocyte subset. To determine if a single lymphocyte population is sufficient to mediate elite control, we will purify lymphocyte subsets from elite controller spleens and transfer these into maPgV-infected Rag-KO mice. In Aim 3, we will generate tools to quantify anti- maPgV immune responses in semi-controllers and elite-controllers. Results from these studies will define the lymp Istituzione: UNIVERSITY OF WISCONSIN-MADISON PI: Adam Lee Bailey Progetto: 5R01AI192811-02

Settori: National Institute of Allergy and Infectious Diseases

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